Two major types of arrhythmias are tachycardias (the heartbeat is too fast—more than 100 beats per minute), and bradycardia (the heartbeat is too slow—less than 60 beats per minute). Arrhythmias can be life-threatening if they cause a severe decrease in the pumping function of the heart. When the pumping function is severely decreased for more than a few seconds, blood circulation is essentially stopped, and organ damage (such as brain damage) may occur within a few minutes. Life threatening arrhythmias include ventricular tachycardia and ventricular fibrillation. Amiodarone or 2-n-butyl 3-[4-(2-diethylaminoethoxy) 3,5-diiodo benzoyl]benzofuran has been approved in an oral tablet form (CORDARONE®) for the treatment of life-threatening ventricular tachyarrhythmias in the United States. This drug is useful not only in treating these arrhythmias but also in treating less severe ventricular arrhythmias and many superventricular arrhythmias including atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways.
Despite the beneficial activities of amiodarone, it is practically insoluble or slightly soluble in an aqueous solvent. Hence, it is difficult to formulate a dosage form suitable for administration. Furthermore, amiodarone has unwanted side effects. For example, treatment can result in hypothyroidism. Amiodarone and its des-ethyl metabolite display an undesirable prolonged residence time in tissues. Amiodarone causes phospholipidosis in the lung, which results in the destruction of macrophages in the alveoli. This destruction is expressed in the patient undergoing treatment with amiodarone by the appearance of pulmonary complications, such as respiratory insufficiency, which require the cessation of treatment. Thus, there is a continuing need for new compounds to treat or prevent arrhythmias and other pathological syndromes of the cardiovascular system.